tbuckley/cabot-search huggingface dataset:
Safety and efficacy of conversion therapy for esophageal squamous cell carcinoma.
Authors: Takayuki Tsuji, Hirofumi Kawakubo, Masashi Takeuchi, Satoru Matsuda, Kazumasa Fukuda, Rieko Nakamura, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2023)

362 Background: The increased efficacy of multimodality treatment allows for the consideration of conversion therapy with curative intent for initially unresectable esophageal squamous cell carcinoma (ESCC) after initial treatment. Conversion therapy has been commonly defined as treatment aiming at a curable intention after tumors initially deemed technically or oncologically unresectable or only marginally resectable respond to chemotherapy. In our institute, conversion therapy is considered for patients with para-aortic lymph node-positive advanced ESCC who have no other distant metastasis, if the para-aortic lymph node metastases have disappeared after systemic chemotherapy. Methods: There were 33 patients of unresectable esophageal cancer with positive para-aortic lymph node metastases from 2011 to 2021. Nine of these patients showed disappearance of para-aortic lymph node metastases and underwent conversion therapy, seven patients underwent esophagectomy and two patients underwent chemoradiation therapy (CRT). Characteristics, short-term and long-term results of these nine cases are studied. Results: All of the nine patients who had para-aortic lymph node metastases were treated with induction DCF (Docetaxel + Cisplatin + 5-FU) therapy as initial treatment. After disappearance of para-aortic lymph node metastasis, minimally invasive or open esophagectomy was performed in seven patients and CRT was performed in two patients. In operation group, four patients (57%) had Clavien-Dindo grade 2 or 3 complications, but no perioperative death was observed. In CRT group, there was no toxicity over CTCAE grade 3. Four of nine patients (44%) had recurrence, within mediastinum lymph node, abdominal lymph node or adrenal gland. 3-year DFS was 56% and 3-year OS was 67%. Conclusions: Conversion therapy is safe and feasible in cases that responded to systemic chemotherapy. Some cases showed good prognosis. Long-term survival is expected with conversion therapy. In our study, there was few cases that could led to conversion therapy. It is expected that more aggressive initial chemotherapy will be used in the future for patients with positive para-aortic lymph node metastases with a view to conversion therapy.
Correlation of high serum interleukin-6 with clinical outcome and T cell response in patients with unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.
Authors: Hongjae Chon, Chan Kim, Hannah Yang, Jaekyung Cheon, Yeonjung Ha, Sung Hwan Lee, Beodeul Kang, Ilhwan Kim, Hyeyeong Kim, Won Suk Lee, Sanghoon Jung, Vince Gaillard
Journal: Journal of Clinical Oncology (2023)

596 Background: We elucidated the clinical and immunologic implications of serum interleukin (IL)-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (Discovery cohort: 84 patients from three centers; Validation cohort: 81 patients from one center). Baseline blood samples were analyzed using a flow cytometric bead array. The tumor immune microenvironment was analyzed using RNA sequencing. Results: In the Discovery cohort, clinical benefit (CB) was defined as a complete or partial response or stable disease for ≥ 6 months. Among various blood-based biomarkers, the serum IL-6 level was significantly higher in patients without CB than in those with CB (mean 11.56 vs. 5.05 pg/mL, P=0.02). The optimal cutoff value for high IL-6 was determined as 18.49 pg/mL using maximally selected rank statistics, and 15.2% of patients were identified to have high IL-6 levels at baseline. In both the Discovery and Validation cohorts, patients with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev compared with that of patients with low IL-6 levels. In the multivariable Cox regression analysis, the clinical implication of high IL-6 levels persisted even after adjustment for various confounding factors. Patients with high IL-6 levels showed reduced interferon-γ and tumor necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and CD8+ T-cell proliferation. Finally, patients with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumor microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment.
A phase Ia/b first-in-human, open-label, multicenter study of BI 905711, a bispecific TRAILR2 agonist, in patients with advanced gastrointestinal cancers.
Authors: James J. Harding, Ralf-Dieter Hofheinz, Elena Elez, Yasutoshi Kuboki, Drew W. Rasco, Michael Cecchini, Lin Shen, Min He, Shorena Archuadze, Niraj Chhaya, Shubham Pant
Journal: Journal of Clinical Oncology (2023)

115 Background: BI 905711 is a tetravalent bispecific antibody that cross-links TRAILR2 with CDH17. This cross-linking drives CDH17-dependent TRAILR2 oligomerization, leading to caspase activation and eventual apoptosis, inhibiting tumor growth in preclinical models of GI cancer. Methods: This Phase Ia/b study of BI 905711 in patients (pts) with advanced GI cancers (NCT04137289) aimed to determine the maximum tolerated dose (MTD) based on the proportion of pts with dose-limiting toxicities (DLT) and explore preliminary antitumor activity. In Phase Ia, pts received BI 905711 every 14 days. One pt with colorectal cancer (CRC) was enrolled at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 pts with CRC were enrolled at each subsequent level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). Up to 4 pts with non-CRC GI cancers were included at the dose level below the CRC cohort. Dose escalation was guided by a Bayesian logistic regression model. Results: As of 01 August 2022, 48 pts (CRC: n = 26; non-CRC: n = 22, including 13 with pancreatic ductal adenocarcinoma [PDAC]) had received BI 905711 (dose range 0.02–4.8 mg/kg); pts had a median age of 61 years (range 27–78) and had received a median of 3 (range 1–11) prior lines of treatment. No DLTs were observed and the MTD was not reached. 41 pts had AEs (grade [G] 3–5: 14 pts; serious: 13 pts). 17 pts had treatment-related AEs (TRAEs); 4 TRAEs were G3: AST increased (2 pts), fatigue and ALT increased (1 pt each). 1 pt had serious TRAEs: G2 decreased appetite and G3 fatigue. 2 pts had G1/2 infusion-related reactions that resolved and did not prevent resumption of treatment. PD biomarker modulation on the level of plasma caspase-3/7 activity was most common at 0.6 mg/kg (4/7 pts) or 1.2 mg/kg (2/6 pts). 13 pts achieved stable disease (SD) and 8 pts were progression-free for ≥4 months (PFS4). In pts with CRC, 6 pts achieved SD and 3 had PFS4. Among non-CRC pts, 7 pts achieved SD (PDAC: n = 6) and 5 had PFS4 (PDAC: n = 4). Median duration of treatment was 30.5 days (range 15–246) overall and 71 days (range 15–211) in the 0.6 mg/kg group (n = 8, predicted therapeutic dose; of whom 3 pts had PFS4: CRC: n = 1/4 [all CDH17+]; non-CRC: n = 2/4). Conclusions: In heavily pretreated pts, BI 905711 was associated with a tolerable safety profile and early signs of disease control. BI 905711 will be further assessed in Phase Ib in 4 dose groups: 0.6/1.2/2.4 mg/kg every 14 days, and 0.6 mg/kg weekly. Clinical trial information: NCT04137289 .
Improvement of a clinical colorectal cancer risk prediction model integrating polygenic risk.
Authors: Erika Leigh Spaeth Tuff, Aviv Gafni, Gillian S. Dite, Richard Allman
Journal: Journal of Clinical Oncology (2023)

81 Background: Improving colorectal cancer risk prediction and stratification is pivotal for implementing better screening and prevention programs in public health and for enabling a personalised approach for assessing patients’ colorectal cancer risk. Methods: In this study, we used the UK Biobank to compare the performance of a risk prediction model incorporating two different polygenic risk scores – one comprising 45 SNPs and the other comprising 140 SNPs. The clinical component of the risk prediction model included a simple measure of first-degree family history. We used age- and sex-specific population incidence rates to calculate full-lifetime risks. Results: The model using the 140-SNP PRS showed an improvement in discrimination, calibration and risk stratification over the model using the 45-SNP PRS for full-lifetime risk: discrimination was 0.706 (95% CI 0.697–0.715) and 0.674 (95% CI 0.664–0.683), respectively, and the P for difference was &lt; 0.001. The 140-SNP model was well calibrated and showed a small overestimation of risk 0.951 (95% CI 0.918–0.986). Standard incidence ratios compared to population incidence rates showed that, for the 140-SNP model, the top quintile of risk shows a 27% improvement compared to the 45-SNP model. Furthermore, there was a 3-fold difference in colorectal cancer incidence between adults identified in the top quintile compared to the bottom quintile of risk using the 140-SNP model versus the 45-SNP model. Conclusions: This updated risk prediction score with a 140–SNP PRS and a simple measure of family history, improves risk prediction and risk stratification in the general population compared with a similar model with a 45-SNP PRS, and will ultimately assist in colorectal cancer disease prevention in the clinic.
Evidence for diet-gene interaction in early-onset colorectal cancer.
Authors: Juanita L. Merchant, Heyu L Song, Elena Martinez Stoffel
Journal: Journal of Clinical Oncology (2023)

182 Background: About 10 percent of all colorectal cancers are in subjects who are not yet 50 (EO-CRC) and the occurrence of early onset colorectal cancer (EO-CRC) is rising in the US. Patients with CRC are twice as likely to have diabetes or be overweight. Using targeted exome sequencing of germline DNA from EO-CRC subjects, we identified a missense mutation at Ala98Val within the DNA binding domain of Hepatic Nuclear Factor 1 alpha (HNF1A, 12q24.31, Rs1800574). HNF1A is the most frequently mutated gene in diabetic individuals whose onset of diabetes occurs typically before age 25 (MODY3 locus). Our aim was to demonstrate that the HNF1A variant provides a genomic landscape for EO-CRC to develop in the setting of a specific diet type. Methods: HNF1A was identified using targeted exon sequencing of archived leukocyte DNA from subjects with EO-CRC. Flag-tagged WT and HNF1A A98V expressing plasmids were transfected into HCT116 colon cancer cells and nuclear extracts were prepared for Electrophoretic Mobility Shift Assays (EMSAs) to test binding differences. An Hnf1a A98V mutant mouse model was generated using CRISPR/Cas9. WT, Hnf1a A98V/+ and Hnf1a A98V/A98V mice were placed on 3 diets--normal chow, a high fat (~34%) diet (HFD) or a high sugar (~62% fructose) diet (HSD) after weaning at 3 weeks. The mice were followed for 12 months, weighed monthly, and observed for clinical signs of morbidity. After euthanizing, blood, colon and liver were collected for histology and qPCR. Results: HNF1AA98V was identified in 13/145 subjects with EO-CRC. An additional 3 subjects exhibited mutations elsewhere in HNF1A. Flag-tagged WT and mutant HNF1A-expressing plasmids were transfected into HCT116 colon cancer cells and nuclear extracts showed reduced HNF1AA98V binding to its consensus DNA element by EMSA. Only heterozygous or homozygous Hnf1a A98V mice on the HFD showed a significant number of colon polyps (~19%). Only 1/22 heterozygous mice developed a polyp on the HSD. RNA-Seq analysis of colonic mucosa from the homozygous mutant compared to WT mice revealed an increase lipid and b-catenin regulated genes. Specifically, there was an increase in β-catenin, LEF 1 and MYC by immunohistochemistry in the polyp of HNF1A A98V , but not in the adjacent normal tissue. Liver steatosis in the Hnf1a A98V versus WT mice on the HFD was observed. Conclusions: Occurrence of the HNF1A A98V variant is increased among a cohort of EO-CRC patients and is a loss of function mutation that creates a genetic landscape for colon polyps on a HFD.
Modified (m)-FOLFOXIRI plus cetuximab versus m-FOLFOXIRI plus bevacizumab as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer: Survival analysis of the phase II randomized DEEPER trial by JACCRO.
Authors: Yu Sunakawa, Manabu Shiozawa, Takanori Watanabe, Hirofumi Ota, Hisateru Yasui, Taichi Yabuno, Mitsuyoshi Tei, Mitsugu Kochi, Dai Manaka, Hisatsugu Ohori, Tatsuro Yamaguchi, Tamotsu Sagawa, Masahito Kotaka, Yutaro Kubota, Takashi Sekikawa, Masato Nakamura, Masahiro Takeuchi, Wataru Ichikawa, Masashi Fujii, Akihito Tsuji
Journal: Journal of Clinical Oncology (2023)

120 Background: Triplet regimen, FOLFOXIRI, plus bevacizumab is considered as one of standard first-line treatments in metastatic colorectal cancer (mCRC). On the contrary, FOLFOXIRI plus anti-EGFR antibody has been shown to be a promising regimen with greater depth of response (DpR) in patients with RAS wild-type mCRC from the VOLFI and MACBETH trials (J Clin Oncol 2019, JAMA Oncol 2018). We therefore performed a randomized phase II study, DEEPER trial (JACCRO CC-13) [NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. We have reported a significantly better DpR of m-FOLFOXIRI plus cet compared to bev as the primary endpoint (Tsuji A, et al. ASCO 2021). Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m 2 , oxaliplatin 85 mg/m 2 , 5-FU 2400 mg/m 2 ) plus cet vs. bev as initial treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05, in per protocol set (PPS) consisted of patients evaluable for the DpR. Secondary endpoints included progression-free survival, overall survival, overall response rate, early tumor shrinkage rate, secondary resection rate, and toxicity. A total of 359 patients were enrolled between July 2015 and June 2019. For the PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), 159 and 162 patients were randomly assigned to the cet and bev arms, respectively. Clinical outcomes will be analyzed according to primary tumor sidedness which is included in the stratification factor. Additionally, we will collect data of BRAF status, and analyze the clinical outcomes in mCRC patients with RAS/ BRAF wild-type tumors and/or left-sided tumors. Pre-planned survival analysis will be performed to compare the two treatment arms at the time of 3 years after last patients’ enrollment using a log-rank test. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant. Statistical analyses will be performed using SAS version 9.4. Clinical trial information: NCT02515734 .
Impact of Lynch syndrome, BRAF<sup>V600E</sup>, and RAS mutations on outcomes in MSI/dMMR metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI): Analysis of combined international cohorts.
Authors: Raphael Colle, Sara Lonardi, Marine Cachanado, Michael J. Overman, Elena Elez, Marwan Fakih, Francesca Corti, Priya Jayachandran, Magali Svrcek, Antoine Dardenne, Alex Duval, Romain Cohen, Filippo Pietrantonio, Thierry Andre
Journal: Journal of Clinical Oncology (2023)

171 Background: ICI have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC . Lynch (LS) vs sporadic (Sp) status, BRAF V600E and RAS mutations (mt) are known factors of clinical and molecular heterogeneity in this population. We aimed to evaluate the prognostic value of these parameters in ICI-treated MSI mCRC pts. Methods: Pts are drawn from international cohorts (France, Italy, Spain, and USA). Pts were considered to have cancer linked to LS only in case of determined germline mutation and Sp in case of loss of MLH1/PMS2 protein expression associated with BRAF V600E mutation and/or hypermethylation of MLH1 promoter, or in case of biallelic somatic mutations of MMR genes. Survival analyses: progression-free survival (PFS) per iRECIST criteria and overall survival (OS) were adjusted on prognostic modifiers, selected on unadjusted analysis (p &lt; 0.2) in case of limited number of events. Results: On the 466 pts included, 112 (24%) received ICI in first line, 305 (65%) received anti-PD1 alone, 161 (35%) anti-PD1 plus anti-CTLA4, 129 (29%) had BRAF V600E mt and 153 (34%) RASmt. Median follow-up was 24.0 months. In adjusted analysis of the whole population (n=466; 186 PFS events and 143 OS events), no association with PFS and OS was observed for BRAF V600E mt (PFS HR 1.20 [0.80 to 1.79], p=0.372; OS HR 1.06 [0.66 to 1.70], p= 0.811) and RASmt (PFS HR 0.93 [0.64 to 1.36], p= 0.712; OS HR 0.75 [0.48 to 1.17] p= 0.202). Adjusting factors were age, ECOG status, number of prior chemotherapies, treatment type (bi vs monotherapy), sidness (right vs left + rectum), primary tumor surgery. Concerning the population with determined Lynch status (n= 242; 83 PFS events and 54 OS events), PFS results are displayed. The analysis of impact of LS was not adjusted on BRAF V600E mutational status due to collinearity. In adjusted analysis, LS improved PFS compared with Sp (HR = 0.49, 95%CI (0.25 to 0.96), p = 0.036). Adjusted HR for OS was 0.56 without reaching significance 95%CI (0.25 to 1.22), p = 0.143. Conclusions: In this analysis of ICI-treated MSI/dMMR mCRC pts, RAS/BRAF V600E mutations are not associated with survival while Lynch syndrome pts demonstrated improved PFS. [Table: see text]
Panitumumab plus trifluridine/tipiracil as third-line anti-EGFR rechallenge therapy in chemo-refractory RAS WT metastatic colorectal cancer: The VELO randomized phase II clinical trial.
Authors: Stefania Napolitano, Vincenzo De Falco, Giulia Martini, Lucia Esposito, Vincenzo Famiglietti, Erika Martinelli, Davide Ciardiello, Francesca Marrone, Antonio Avallone, Claudia Cardone, Alfonso De Stefano, Vincenzo Montesarchio, M. Giulia Zampino, Roberto Bordonaro, Mario Scartozzi, Daniele Santini, Massimo Di Maio, Fortunato Ciardiello, Teresa Troiani
Journal: Journal of Clinical Oncology (2023)

129 Background: Rechallenge therapy with epidermal growth factor receptor (EGFR) inhibitors in chemo-refractory metastatic colorectal cancer (mCRC) is an emerging therapeutic approach. Trifluridine-tipiracil is approved for treatment of chemo-refractory mCRC patients. Methods: Chemo-refractory RAS WT mCRC patients, that had a major response (partial or complete response) to first-line chemotherapy plus an anti-EGFR monoclonal antibody and had an-anti-EGFR drug-free interval during second-line therapy of four or more months were randomized in a phase II trial to assess the addition of the anti-EGFR monoclonal antibody panitumumab to trifluridine-tipiracil as third-line rechallenge therapy. The primary endpoint was progression free survival (PFS). Baseline plasma was analyzed for circulating free tumor (ct) DNA by using Biocartis Idylla platform to detect mutations in KRAS, NRAS, BRAF ( V600E) and EGFRextracellular domain ( S492R). In 24 patients with baseline RAS/BRAF wild type (WT) ctDNA, Foundation One liquid CDx (324 gene profiling) was also performed before treatment and at disease progression. Results: 62 patients were treated with trifluridine-tipiracil (31 patients, arm A) or with trifluridine-tipiracil plus panitumumab (31 patients, arm B). As of September 16, 2022, 1 patient in arm A and 2 patients in arm B were on treatment. The primary endpoint was met. Median PFS (mPFS) was 4 months in arm B versus 2.5 months in arm A [hazard ratio (HR): 0.48; 95% CI 0.28-0.82; P = 0.007]. Baseline plasma RAS/BRAF WT ctDNA was found in 23/31 patients in Arm A and in 26/31 patients in Arm B. In this group, mPFS was 4.5 months in Arm B versus 2.6 months in Arm A (HR: 0.48; 95% CI 0.26-0.89; P = 0.019). Disease control (major responses plus stable disease) was higher for patients in Arm B compared to Arm A (81% versus 48%), whereas disease progression was the best response in 19% versus 52% patients, respectively. PFS rates at 6 and 12 months were 38.5% and 15.4% in arm B versus 13% and 0% in arm A. At disease progression, Foundation One liquid CDx detected several mutations within the EGFR pathway, which could correlate with cancer cell resistance to panitumumab. Conclusions: This is the first prospective randomized trial which evaluated anti-EGFR monoclonal antibody (panitumumab) in addition to standard of care (trifluridine-tipiracil) as third-line rechallenge therapy in chemo-refractory RASWT mCRC patients. Baseline liquid biopsy allows selection of RAS/BRAF WT ctDNA patients who could have a relevant clinical benefit. Clinical trial information: NCT05468892 .
Comparative analysis of tumor immune microenvironment in primary tumors vs metastatic tissue in microsatellite stable metastatic colorectal cancer.
Authors: Marwan Fakih, Jian Ye, Chongkai Wang, Arya Ashok, Elizabeth Mauer, Calvin Y. Chao
Journal: Journal of Clinical Oncology (2023)

187 Background: We previously demonstrated differences in responses to checkpoint inhibitors between liver and non-liver metastases (mets) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Here, we investigate differences in tumor microenvironment (TME) and mutational landscape of primary and mCRC sites. Methods: We used the Tempus clinicogenomic database to select de-identified cases of MSS mCRC which underwent Tempus xT testing. Tempus xT is a 648-gene NGS panel that detects somatic alterations and includes RNA sequencing. Gene expression patterns of different immune cells were used to predict their relative abundance within the tumor. Analyzed tumors were divided into 4 categories based: primary tumor (colon), liver, lung, and peritoneal mets. Demographics, genomic alterations, tumor mutational burden (TMB), PD-L1 expression, and proportions of B, T (CD4+, CD8+), NK cells, and macrophages were compared between all 4 categories. Chi-squared/Fisher’s exact tests or Kruskal-Wallis tests were used to assess statistical significance. Results: Genomic profiles from 4,345 unique mCRC patients were analyzed (Primary CRC = 1734; Liver = 1825; Lung = 443; Peritoneal = 343). Median TMB and PD-L1 expressions had small differences across sites that were statistically significant. KRAS mutations were more frequent and SMAD4 mutations were less prevalent in lung mets. RNA-Seq revealed significant differences in immune cell composition. Lung mets exhibited a higher percentage of B cells and lower percentage of macrophages than liver and peritoneum (p&lt; 0.001), similar to primary tumors. CD4+ T cells were highest in primary tumors, whereas CD8+ T cells were highest in lung mets (p &lt; 0.001). Conclusions: The TME of lung mets has a more favorable immune composition (increased CD8+ T cells and B cells, decreased macrophages) than that of liver and peritoneal mets, suggesting that MSS mCRC to the lung may potentially be more responsive to immunotherapy.[Table: see text]